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Association between genetic variants in VEGF, ERCC3 and occupational benzene hematotoxicity
  1. H Dean Hosgood III (hosgoodd{at}mail.nih.gov)
  1. National Cancer Institute, United States
    1. Luoping Zhang
    1. National Cancer Institute, United States
      1. Min Shen
      1. National Cancer Institute, United States
        1. Sonja I Berndt
        1. National Cancer Institute, United States
          1. Roel Vermeulen
          1. Utrecht University, Netherlands
            1. Guilan Li
            1. Chinese Center for Disease Control and Prevention, China
              1. Songnian Yin
              1. Chinese Center for Disease Control and Prevention, China
                1. Meredith Yeager
                1. National Cancer Institute, United States
                  1. Jeff Yuenger
                  1. National Cancer Institute, United States
                    1. Nathaniel Rothman
                    1. National Cancer Institute, United States
                      1. Stephen Chanock
                      1. National Cancer Institute, United States
                        1. Martyn Smith
                        1. University of California, Berkeley, United States
                          1. Qing Lan
                          1. National Cancer Institute, United States

                            Abstract

                            Benzene is an established human hematotoxin, with substantial interindividual variation in benzene-induced toxicity. To further examine if genetic variation contributes to benzene hematotoxicity, we analyzed 1,023 tagSNPs in 121 gene regions important for benzene metabolism, hematopoiesis, leukemia, and lymphoma among 250 benzene-exposed workers and 140 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyze the relationship between genetic polymorphisms and total white blood cell (WBC) count and its subtypes, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. The minP test assessed the association on the gene region level. The False Discovery Rate method controlled for multiple comparisons. VEGF (minP = 0.0030) and ERCC3 (minP = 0.0042) were the most significantly associated gene regions with altered WBC counts among benzene-exposed workers, after accounting for multiple comparisons. Highly significant changes were also found for WBC subtype counts, including granulocytes, CD4+ T cells, and lymphocytes for VEGF and granulocytes and NK cells for ERCC3. In workers exposed to <1ppm, a SNP in VEGF was associated with changes in WBC and granulocyte counts, and SNPs in ERCC3 were associated with changes in WBC, NK cell, and granulocyte counts. Our findings suggest that genetic variation in VEGF, which is critical to blood vessel growth, and ERCC3, which is a member of the DNA repair pathway and is responsible for repairing bulky DNA damage formed by chemicals, may contribute to individual susceptibility to benzene-induced hematotoxicity at relatively low levels of benzene exposure.

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